Magnetic resonance imaging indicators for neurological outcome after surgery in patients with intramedullary spinal ependymomas

Abstract This is a retrospective study. The aim of this study was to determine the indicators of neurological outcome after surgery in patients with intramedullary spinal ependymomas by using magnetic resonance imaging (MRI). A total of 106 consecutive patients (mean age: 42.4 ± 1.3 years; 52.8% male) diagnosed with intramedullary spinal ependymomas were retrospectively recruited. All patients underwent spine MRI and subsequent surgical resection for the spinal tumors. Data regarding clinical symptoms and pathological grades of tumors were collected from clinical records. The McCormick score was used for grading patients’ neurological status before and after surgery at 12 months. Good outcome was defined as stable McCormick score (McC) score (no change of McC score between preoperation and post-operation at 12 months) or improvement in McC score (post-operative McC score at 12 months < preoperative McC score). Poor outcome was determined when there was an increase in McC score at 12 months after surgery. The MRI characteristics of spinal ependymomas between patients with good and poor neurological outcomes were compared. Logistic regression was performed to assess the association between MRI characteristics of tumors and post-operative neurological outcomes. Patients with poor neurological outcomes had larger longitudinal length (4.7 ± 0.5 vs 3.3 ± 0.2, P = .004) and higher enhancement signal-to-noise-ratio (SNR) (102.4 ± 12.3 vs 72.8 ± 4.6, P = .022) than those with good neurological outcomes. After adjusting for confounding factors, longitudinal length (OR, 0.768; 95% CI, 0.604–0.976; P = .031) and enhancement SNR (OR, 0.988; 95% CI, 0.978–0.999; P = .026) of spinal ependymomas were significantly associated with poor neurological prognosis. The longitudinal length of tumor and enhancement SNR on T1-weighted images are independently associated with neurological outcome after surgery.


Introduction
Intramedullary spinal cord tumors (IMSCT) are very rare, accounting for only 2% to 4% of all central nervous system (CNS) tumors. [1] Of these, ependymomas are the most commonly encountered tumors. [2] Currently, surgical resection is the mainstream treatment modality for spinal ependymomas. The goal of surgery is to maintain or improve neurological function and ensure maximal safe resection of the tumor. A substantial number of retrospective studies on intramedullary spinal ependymomas in the last decade have reported that various factors may be predictive for neurological outcomes after surgery, including age, sex, duration of symptoms before surgery, preoperative neurological status, extent of tumor removal, pathological World Health Organization (WHO) grade, tumor size, tumor location, and tumor margins. [3][4][5][6][7][8][9][10] However, most existing studies have smaller sample size and the evidence on the role of the above-mentioned influencing factors in neurological outcomes is controversial. Magnetic resonance imaging (MRI) is now recognized as an ideal modality for assessing the characteristics of spinal ependymomas in clinical settings, because MRI provides multidimensional and multi-contrast information of tumors. However, a comprehensive and quantitative evaluation of the MRI features of intramedullary spinal ependymomas and their association with postoperative neurological outcomes is still lacking. The purpose of this retrospective study was to determine the association between MRI characteristics of intramedullary spinal ependymomas at baseline and the 1-year neurological outcome after surgery.

Study population
Patients who underwent surgery for spinal ependymomas and MRI before the surgery between January 2015 and June 2018 were retrospectively recruited. Patients with myxopapillary ependymomas were excluded in this study, because these tumors are located in the filum terminalis and, by definition, are not intramedullary tumors. Patients who failed to be followed-up for at least 12 months or had contraindications to MRI examination were excluded. The clinical information including age, sex, duration of clinical symptoms, and tumor grades determined by pathology was collected from medical records. All patients presenting with neurological clinical features were evaluated thoroughly by academic residents of neurosurgery.  [2] The study protocol was approved by the institutional review board, and written consent form was obtained for each patient.

Operative and perioperative course
All patients underwent their first operation at our institution. The operation followed the usual procedures for intramedullary spinal cord tumors. [11] Intraoperative neurophysiological monitoring (IOM) was regularly used to monitor all cases. [12] An operating microscope was routinely used in all operations. There was no peri-or intraoperative radio-or chemotherapy used. The excised tumor mass was then examined by 2 senior pathologists concurrently to arrive at a histological diagnosis.

MR image analysis
Two experienced neuroradiologists (M.Y., Z.Z.) with >5 years' experience in neuroimaging and blinded to the histopathological results independently evaluated the MR images with consensus. During MR image analysis, the following features were analyzed using the picture archiving and communication system (PACS) workstation: 1. longitudinal length of the tumor which was defined as the number of vertebrae that the tumor covers; 2. Signal-to-noise-ratio (SNR) on T2WI which was defined as the ratio of the signal of tumor at the region with homogenous intensity to the noise of air; 3. enhancement patterns which were categorized into no enhancement, homogenous enhancement, and inhomogeneous enhancement; 4. enhancement SNR which was defined as the ratio of the signal of tumor at the region with enhancement to the noise of air; 5. clearness of tumor margin; 6. presence of cyst; 7. presence of hemorrhage; 8. presence of peripheral edema; and 9. tumor location.
The clearness of tumor margin was determined according to the boundaries between the tumor and surrounding spinal cord. The presence of hemorrhage was defined as hyperintense within the tumor on T1W imaging with fat saturation (signal intensity >1.5 times that of the adjacent spinal cord). Peripheral edema was defined as presence of hyperintense signal surrounding the lesions on T2WI without enhancement on T1WI.

Clinical follow-up
All patients underwent MRI preoperatively, 48 hours postoperatively, and then every 6 months until the last follow-up. The extent of the excision was graded into: gross-total resection (GTR) (no residual enhancement on initial postoperative MRI) and subtotal resection (STR) (<20% residual enhancement on initial postoperative MRI). The neurological status of all patients was also evaluated at discharge, 6 months, and 12 months after surgery. The neurological outcomes were classified into "good" and "poor" categories. Good outcome was defined as stable McCormick score (McC) score (the McC score does not change between pre-and post-operation at 12 months) or improvement in McC score (postoperative McC score at 12 months < preoperative McC score). Poor outcome was determined when there was an increase in McC score at 12 months after surgery.

Statistical analysis
Statistical Package for the Social Sciences version 11.0 (SPSS, Chicago, IL) and STATA 14.0 were used for statistical analysis. Means and standard deviation were calculated for continuous data with normal distribution. If the continuous variables showed non-normal distribution after normality test, the nonparametric Wilcoxon rank-sum test was used for the median comparison between the 2 groups. Median was also calculated for continuous data with non-normal distribution. Percentages and proportions were calculated for categorical data. Chi-Squared test was used to determine the differences in categorical variables between patients with good and poor neurological outcome. Univariate and multivariate logistic regressions were performed to assess the correlation between MRI characteristics of the tumor and postoperative neurological outcomes before and

Results
The mean age of the 106 recruited patients was 42  Table 1 summarizes the clinical and MRI characteristics of the study population. Of the 106 ependymomas, 72 (67.9%), 23 Table 1 Clinical and MR imaging characteristics of study population (n = 106).

MRI characteristics
Mean ± SD and Median or n (%)

Association between MRI characteristics and neurological outcome
The results on the association between tumor characteristics and neurological outcome are detailed in Table 2 Figure 1 depicts the imaging findings in a patient who had high enhancement SNR in an ependymoma and suffered from poor neurological outcome. Figure 2 showed the imaging features of a patient who had low enhancement SNR in an ependymoma and good neurological outcome. Figure 3 shows the imaging features of a patient who had a long ependymoma and high enhancement SNR and suffered from poor neurological outcome.

Discussion
This study investigated the association between MRI characteristics of tumors and postoperative neurological outcomes in patients with intramedullary spinal ependymomas. We found that the tumor length and enhancement SNR on T1W images were significantly associated with neurological outcome after surgery, before and after adjusting for confounding factors. Our findings suggest that patients with larger length or higher enhancement SNR of intramedullary spinal ependymomas may have poor neurological outcome after surgery. In the present study, patients with larger tumor length had poor outcome after surgery. This is in agreement with the study by Ebner et al, which also confirmed that patients with extended intramedullary lesions have a worse neurological status preoperatively, postoperatively and in the 3-month follow-up. In the study by Ebner et al, 46 patients were recruited and divided into group A (lesions fewer than 3 vertebral segments) and group B  www.md-journal.com (lesions over 3 or more vertebral segments). Their results showed that patients in group B had significant lower preoperative McCormick and Klekamp-Samii grades than those in group A with P < .05. [7] Peker et al analyzed 21 cases of intramedullary ependymomas and concluded that longer length was significantly associated with development of dysesthesia postsurgery. [13] This may be because a large-sized tumor leading to rupture of the tumor capsule and subsequent infiltration of surrounding neural tissue, intraoperative traction, and detachment may result in new deficits after surgery; hence, once the normal plasticity of the spinal cord is impaired because of extrusion by a large tumor, surgery offers few advantages with regard to neurological improvement. [14,15] On pre-contrast MRI, intramedullary spinal ependymomas usually show high signal intensity on T2W images. On contrastenhanced T1W images, most tumors show homogeneous enhancement and often have clear margins. [16] However, the MR signal intensity (SI) and degree of enhancement are variable owing to the different distributions of the vascular component of the connective tissue in the tumor mass. [17] Chang et al found no significant association between MRI signal features and enhancement patterns and postoperative neurological outcome of intramedullary spinal ependymomas. [18] However, quantitative evaluation of MR SI and enhancement degree of intramedullary spinal ependymoma in the evaluation of association with postoperative neurological outcomes is still lacking. In our study, we quantitatively evaluated MR SI on T2W images and contrast-enhancement degree on T1W images using SNR. We found that enhancement SNR in the poor neurological outcome group was significantly higher than that in the good neurological outcome group. Enhancement SNR is the ratio of the tumor signal at the region with enhancement to the noise of air, which reflects the degree of enhancement. Contrast enhancement of tumors reflects not only microvascular proliferation of the tumor lesion but also disrupted blood-brain barrier. [19,20] The possible mechanism is that intramedullary spinal ependymomas with higher degree enhancement may have more feeding branches of the anterior spinal cord artery for both the tumor and peripheral spinal cord. After these feeders were coagulated and severed, peripheral spinal cord ischemia may be more serious. Our results did not show significant difference in SNR on T2W images between the poor and good postoperative neurological outcome groups.
In the present study, patients with higher pre-operative McC score were more likely to have poor neurological outcomes after surgery, though preoperative McC score was not an independent indicator for neurological outcome. Our findings are consistent with literature reports. [6,21,22] In the study by Chang et al, of 31 patients with spinal enpendymomas, 11 (35%) with preoperative Nurick's grade < 4 showed improvement in neurological status, whereas those with preoperative Nurick's grade = 4 showed poorer neurological status (P = .05). This study suggested that patients with worse preoperative neurological statuses had fewer opportunities for neurological improvement. [18] Furthermore, early diagnosis and timely microsurgical management have been suggested to be vital for positive outcomes. [10,18] Most reports acknowledge that high-grade intramedullary spinal cord tumors had higher rates of recurrence but no effect on neurological outcome. [23] Our findings are consistent with literature reports. The ependymal tumors were classified into 3 types according to WHO criteria: grade I: subependymoma or myxopapillary ependymoma (MPE); grade II: ependymoma (E II); and grade III: anaplastic ependymoma (AE III). [24] Myxopapillary ependymomas growth in the filum terminalis are extramedullary tumors and can be resected with less morbidity compared to truly intramedullary ependymomas. Patients with myxopapillary ependymomas were excluded in this study. Benefiting from the application of neurophysiological monitoring and microneurosurgical techniques in the surgery, in the present study, although GTR was achieved in all 4 patients with highgrade anaplastic ependymomas, 3 (75.0%) patients experienced recurrence because of malignancy of this type of tumor.
Previous studies have indicated that age, sex, duration of symptoms before surgery, tumor location, tumor margins, and the extent of tumor removal can be prognostic factors for neurological outcomes. [3,5,9,10,14] In contrast, no significant association was found between all these factors and the neurological outcomes in our study. Previous investigators believe that tumor location and tumor margins may not be the independent prognostic factors that usually influence the extent of tumor removal. Most reports acknowledge that the extent of tumor removal was the most significant prognostic factor influencing the postoperative outcome. Clearly, complete surgical resection is the best choice of treatment with a favorable outcome. Nevertheless, neurological outcome was not significantly affected by the extent of tumor resection (P = .966) in the present study. This possible reason might be limited by the number of cases with STR (5 cases, 4.7%).
Our study has some limitations. First, this is a single-center study with a relatively small number of anaplastic ependymoma (WHO grade III) patients. Second, this is a non-randomized trial lacking a control group and hence, we were unable to compare the outcomes between patients who did or did not undergo operation.

Conclusion
The longitudinal length and enhancement SNR on T1WI of intramedullary spinal ependymomas are independently associated with neurological outcome after surgery. Our findings suggest that patients with larger length tumor or higher enhancement SNR of intramedullary spinal ependymomas may have poor neurological outcome after surgery than other patients.

Ethics statement
Study participants voluntarily agreed to participate in the study and provided written informed consent before enrollment. The study was approved by the Ethics Committee of Beijing Tsinghua Changgung Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.